Summary? Rethinking the zinc-copper relationship in Wilson Disease Wilson Disease is an inherited disorder of copper metabolism that impacts an estimated 1:30,000 people. The disease is caused by mutations in the ATP7B copper transporter that leads to pathologic and ultimately lethal copper accumulation in tissues, particularly in the liver and brain. Though the genetic cause of Wilson Disease is known, the underlying mechanisms by which copper overload causes disease is still poorly defined. Copper accumulation is expected to induce oxidative damage to cellular structures; though this mechanism appears to be more apparent later in disease progression, while the early and copper-specific molecular effects of copper accumulation remain elusive. Therapies for Wilson Disease include consumption of a low-copper diet, treatment with de-coppering drugs and zinc supplementation. Zinc supplementation is thought to limit copper absorption by a competition and buffering effect in the intestinal cells, whereby copper is eliminated through natural turnover of the intestinal lining. Our recent work and that of others indicates that zinc-dependent proteins are specifically affected in Wilson Disease, with important physiological impacts on lipid metabolism. Our preliminary data has made novel observations in the genetically-engineered mouse model of Wilson Disease that reveal zinc homeostasis and zinc-dependent processes are disrupted by excess copper. We observed that zinc acquisition machinery is activated in the liver and the liver of the Wilson Disease mouse accumulates excess zinc alongside of copper. This work is undertaken to understand the copper-zinc interaction in Wilson Disease and how clinical therapies impact zinc-dependent systems. The results of the work have potential to inform and improve treatment of Wilson Disease.